Pharmacokinetic overview of Ortho Evra /Evra

Transcription

1 FERTILITY AND STERILITY VOL. 77, NO. 2, SUPPL 2 FEBRUARY 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Pharmacokinetic overview of Ortho Evra /Evra Larry S. Abrams, Ph.D., Donna Skee, M.S., Jaya Natarajan, Ph.D., and Frankie A. Wong, M.S. Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey Objective: The pharmacokinetics of norelgestromin, the primary active metabolite of norgestimate, plus ethinyl estradiol (EE), delivered by the once-weekly contraceptive patch (Ortho Evra /Evra ), have been studied in eight trials. This overview summarizes the relevant pharmacokinetic data for the contraceptive patch. Design: Review article. Result(s): The amount of norelgestromin and EE absorbed from the patch is proportional to patch size: the 20-cm 2 patch (Ortho Evra ) delivers norelgestromin, 150 g/d, and EE, 20 g/d, to the systemic circulation. After single and multiple applications of the contraceptive patch, daily serum concentrations (area under the serum concentration-versus-time curve) of norelgestromin and EE were within the ranges generally seen with oral norgestimate, 250 g/ee 35 g (Ortho-Cyclen /Cilest ), but without the peaks and troughs characteristic of oral dosing. Moreover, the contraceptive patch maintains serum concentrations of norelgestromin and EE within these ranges for up to 10 days, suggesting that clinical efficacy would be maintained even if a scheduled change is missed for as long as two full days. Regardless of the location of patch application (abdomen, buttock, upper outer arm, or torso [excluding breasts]) and even under conditions of heat, humidity, exercise, and cool-water immersion, efficacious concentrations of norelgestromin and EE are achieved. Coadministration of the patch with tetracycline did not affect the pharmacokinetics of norelgestromin and EE. Conclusion(s): The contraceptive patch exhibits an excellent pharmacokinetic profile, maintaining efficacious serum hormone concentrations under varying conditions. (Fertil Steril 2002;77(Suppl 2):S by American Society for Reproductive Medicine.) Key Words: Ethinyl estradiol, norelgestromin, Ortho Evra, Evra, contraception, transdermal contraception, contraceptive patch, pharmacokinetics Received November 5, 2001; revised and accepted December 12, Supported by The R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, now known as Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Reprint requests: Larry S. Abrams, Ph.D., Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 920 Route 202, P.O. Box 300, Raritan, New Jersey (FAX: ; labrams@prius.jnj. com) /02/$22.00 PII S (01) Ortho Evra /Evra is a novel transdermal contraceptive patch recently developed by The R.W. Johnson Pharmaceutical Research Institute. The patch is a 20-cm 2, three-layer system comprising an outer protective layer, a medicated adhesive layer, and a clear release liner that is removed before patch application. Two active ingredients are released from the transdermal system. The progestin component is norelgestromin, previously known as 17- deacetylnorgestimate, which is the primary active metabolite of norgestimate (the progestin used in the oral contraceptives Ortho-Cyclen and Ortho Tri-Cyclen ) (1, 2). The estrogen component is ethinyl estradiol (EE). When applied to the skin, the patch delivers norelgestromin, 150 g/d, and EE, 20 g/d, to the systemic circulation (3). Because the patch is a transdermal delivery system, the doses of estrogen and progestin delivered cannot be compared with the doses of estrogen and progestin in an oral contraceptive. Recommended dosing is one patch applied once weekly for three consecutive weeks (21 days), followed by 1 patch-free week per cycle. Patches should be removed or changed on the same day each week. Various pharmacokinetic aspects of interest for the contraceptive patch have been studied and reported in the literature. Trials have evaluated dose proportionality in relation to patch size, bioavailability, and pharmacokinetics after single and multiple applications, application at various sites, and under varying conditions of wear (heat, humidity, exercise, and coolwater immersion). In all of the studies discussed here, serum concentrations of norelgestromin and EE were determined by using validated methods described elsewhere S3

2 (4 7). The objective of this overview is to summarize the relevant pharmacokinetic data for the contraceptive patch. REFERENCE RANGES The reference concentration ranges of norelgestromin and EE for the contraceptive patch that are described in this overview were calculated from the average serum concentrations in 90% of participants (excluding the upper and lower 5%) taking Ortho-Cyclen/Cilest (oral norgestimate, 250 g, plus EE, 35 g) in a pharmacokinetic study (data on file, Johnson & Johnson Pharmaceutical Research and Development, L.L.C.) (Table 1). This was computed from AUC 0- / for these compounds at steady-state concentrations over a 24-hour period after administration of the norgestimate/ee oral contraceptives. The reference ranges are 0.6 to 1.2 ng/ml for norelgestromin and 25 to 75 pg/ml for EE. The reference ranges are not necessarily the upper and lower limits of the therapeutic concentration ranges for the patch; rather, they were established as a developmental tool to identify efficacious concentrations of norelgestromin and EE. Steady-state concentrations (C ss ) after transdermal administration and average serum concentrations after oral administration are pharmacokinetically distinct variables that cannot be directly compared. However, such a comparison is valid as a developmental tool. PHARMACOLOGIC ACTIVITY OF THE CONTRACEPTIVE PATCH The pharmacologic activity of both components of the contraceptive patch is related to the amount of serum sex hormone binding globulin (SHBG) circulating in the body. Estrogens such as EE cause a marked increase in SHBG TABLE 1 Steady-state pharmacokinetics of norelgestromin and ethinyl estradiol following three cycles of administration of Ortho-Cyclen. Parameter Norelgestromin Ethinyl estradiol a C max a C ave b AUC 0 24h c t 1/ [ ] d [25 75] d , Note: Data are means ( SD). AUC area under serum concentrationversus-time curve; C ave AUC 0 24 /24; C max maximum serum concentration; t 1/2 elimination half-life. a Obtained on day 21 of cycle 3. Norelgestromin is expressed in ng/ml; ethinyl estradiol is expressed in pg/ml. b Obtained on day 21 of cycle 3. Norelgestromin is expressed in h ng/ml; ethinyl estradiol is expressed in h pg/ml. c Obtained on days of cycle 3; units: h. d Range for 90% of participants, excluding upper and lower 5%. Data on file, Johnson & Johnson Pharmaceutical Research & Development, L.L.C. levels (8, 9). Endogenous sex steroids and most 19-nortestosterone derivatives bind to SHBG with high affinity (10). Therefore, when combination hormonal products containing EE are administered, levels of SHBG increase, which increases the amount of SHBG-bound progestin (for progestins bound to SHBG) and decreases the amount of non protein-bound progestin. A decrease in non protein-bound progestin leads to a decrease in pharmacologic activity. As indicated earlier, norelgestromin is the primary active metabolite of norgestimate. Norgestrel is a secondary active metabolite that adds little pharmacologic activity (2). The TABLE 2 Pharmacokinetics of norelgestromin and ethinyl estradiol following single application of different patch sizes. 10-cm 2 patch 15-cm 2 patch 20-cm 2 patch Norelgestromin C ss, ng/ml AUC 0 168h,ng h/ml AUC 0 240h,ng h/ml a Ethinyl estradiol C ss (pg/ml) b b b AUC 0 168h,pg h/ml 4,253 1,668 6,022 2,181 8,543 3,488 AUC 0 240h,pg h/ml b 4,663 1,786 6,657 2,372 9,395 3,828 Note: Data are means ( SD). AUC area under serum concentration-versus-time curve; C ss steady-state serum concentrations. a Dose proportionality was indicated by the confidence intervals (CI) for dose-normalized AUC values for norelgestromin. 90% CI for the ratio of the mean AUC 0 240h were as follows: 10 cm 2 /20 cm 2, % %; 15 cm 2 /20 cm 2, 92.11% %; 10 cm 2 /15 cm 2, % %. b Dose proportionality was indicated by the CI for dose-normalized AUC values for ethinyl estradiol. 90% CI for the ratio of the mean AUC 0 240h were as follows: 10 cm 2 /20 cm 2, 93.25% %; 15 cm 2 /20 cm 2, 91.00% %; 10 cm 2 /15 cm 2, 95.48% %. Data on file, Johnson & Johnson Pharmaceutical Research & Development, L.L.C. S4 Abrams et al. Contraceptive patch pharmacokinetics Vol. 77, No. 2, Suppl 2, February 2002

3 TABLE 3 Pharmacokinetics of norelgestromin and ethinyl estradiol after intravenous infusion and application of the contraceptive patch. Route of administration Parameter Norelgestromin Ethinyl estradiol Intravenous infusion a Clearance (L/h) t 1/2 (h) Contraceptive patch b C ss c t 1/2 (h) k 0 ( g/d) t 1/2 elimination half-life; C ss steady-state serum concentrations; k 0 absorption rate. Note: Data are means ( SD). a Intravenous infusion of 252 g of norelgestromin and 25 g of ethinyl estradiol over a 1-hour period. b Abdomen and buttock sites of application; data combined. c Norelgestromin is expressed in ng/ml; ethinyl estradiol is expressed in pg/ml. Data on file, Johnson & Johnson Pharmaceutical Research & Development, L.L.C. activity of norelgestromin versus norgestrel can be related to the binding of these hormones to SHBG. Whereas most sex steroids, including norgestrel, bind to SHBG, norelgestromin does not; changes in SHBG levels during treatment (i.e., increased levels of SHBG caused by EE) therefore do not affect the serum distribution of norelgestromin (10). Because a greater amount of norelgestromin is non protein bound and available for biologic activity and because norgestrel is primarily bound by SHBG and is unavailable to target tissue, these data indicate that norelgestromin accounts for most of the progestogenic activity of the contraceptive patch (unpublished observations). DOSE PROPORTIONALITY An open-label, randomized, three-period, crossover, dose proportionality study (29 patients) evaluated three patch sizes: 10 cm 2,15cm 2, and 20 cm 2 (11). Patches were applied to the lower abdomen for 7 days, with a 1-month washout period between treatments. Serum samples were analyzed for norelgestromin and EE up to 240 hours after each patch application. The patch was removed after the 168-hour sample, and C ss were calculated between 48 and 168 hours. The daily serum concentration (area under the serum concentration-versus-time [AUC] curve) was also estimated. The confidence intervals for dose-normalized AUC ratios for norelgestromin and EE for the 10-, 15-, and 20-cm 2 patches were within the 80% 125% acceptability range, indicating dose proportionality (Table 2) (11). The percentage of persons achieving C ss at or above the targeted reference range for the 10-, 15-, and 20-cm 2 patches, respectively, was 10.3%, 58.6%, and 89.7% for norelgestromin and 62.1%, 89.7%, and 96.6% for EE. On the basis of these findings, we conclude that the 10-cm 2, 15-cm 2, and 20-cm 2 patches are dose proportional. BIOAVAILABILITY OF THE CONTRACEPTIVE PATCH An open-label, randomized, parallel, two-way crossover study (26 participants) evaluated the bioavailability of norelgestromin and EE from the contraceptive patch relative to a single intravenous infusion of norelgestromin, 252 g, and EE, 25 g, for 60 minutes (3). The patch was worn on the abdomen in one group and on the buttock in the other group for 7 days. There was a 1-month washout phase between treatments. Blood samples were drawn before and up to 240 hours after patch application or before and up to 72 hours after the start of the intravenous infusion. The mean absorbed dose of norelgestromin/ee was determined by the following equation: k 0 CL C ss where k 0 is the absorption rate, CL is the clearance of norelgestromin/ee after intravenous infusion, and C ss is the steady-state serum concentration of norelgestromin or EE after patch application (3). The k 0 of norelgestromin or EE did not significantly differ between the abdomen and buttock sites of application; thus, the overall mean (average of both sites) concentration was calculated. The contraceptive patch systemically delivers mean concentrations of 150 g/d of norelgestromin and 20 g/d of EE (Table 3), which achieves concentrations within the reference range for both hormones. SINGLE APPLICATION OF THE CONTRACEPTIVE PATCH In an open-label study (18 participants), participants wore the contraceptive patch on the abdomen for 7 days to determine the pharmacokinetic profiles of norelgestromin and EE after a single application (12). Blood was drawn 2 hours before and up to 288 hours after patch application; the patch was removed after the 168-hour sample was drawn. Serum concentrations of norelgestromin and EE remained within the reference range during the entire 7-day wear FERTILITY & STERILITY S5

4 FIGURE 1 (A), Mean serum concentration-versus-time profile of norelgestromin and ethinyl estradiol (EE) after a single 7-day patch application. (B), Mean serum concentration-versus-time profile of norelgestromin and EE after administration of the oral contraceptive Ortho-Cyclen. Data for the patch and oral contraceptive are from two separate trials (data on file, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.). period (Figure 1A). The serum concentration profile of the patch differs from that of oral contraceptives, such as Ortho- Cyclen (Figure 1B) (data on file, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.). Although this was not a comparative trial between the two agents, Figure 1A illustrates that the contraceptive patch maintains steady drug concentrations within the reference range without the peaks and troughs that are characteristic of oral contraceptives (Figure 1B). MULTIPLE APPLICATIONS OF THE CONTRACEPTIVE PATCH 7-Day Application Versus 10-Day Application An open-label study (12 participants) was conducted to determine the pharmacokinetics of norelgestromin and EE after two consecutive applications of the contraceptive patch, the first for 7 days (proper dosing) and the second for 10 days (a 3-day dosing error) (6). The site of application for both the 7-day and 10-day (i.e., 3 days beyond the intended 7-day wear period) wear periods was the abdomen. The second patch was removed 408 hours (day 17) after the start of the study. Blood samples were drawn immediately before patch application and at multiple time points up to and including 2 days after removal of the second patch. The mean serum concentrations of norelgestromin and EE remained within the reference range for the entire 7-day wear period after application of the first patch and for the 10 days after application of the second patch (Figures 2 and 3) (6). Although mean serum hormone concentrations decreased slightly at the time of patch change, they still remained within the reference range for both norelgestromin and EE. Concentration ratios showed little or no accumulation ( 20%) of norelgestromin or EE. These findings suggest S6 Abrams et al. Contraceptive patch pharmacokinetics Vol. 77, No. 2, Suppl 2, February 2002

5 FIGURE 2 Mean serum concentration-versus-time profile of norelgestromin during the first patch application (0 168 hours, or days 0 7), the second patch application ( hours, or days 7 17), and the terminal elimination phase ( hours, or days 17 19). Dashed horizontal lines indicate the reference range. Vertical lines indicate the time of patch application or removal. Reprinted with permission (6). FIGURE 3 Mean serum concentration-versus-time profile of ethinyl estradiol (EE) during the first patch application (0 168 hours, or days 0 7), the second patch application ( hours, or days 7 17), and the terminal elimination phase ( hours, or days 17 19). Dashed horizontal lines indicate the reference range. Vertical lines indicate the time of patch application or removal. Reprinted with permission (6). FERTILITY & STERILITY S7

6 FIGURE 4 Mean serum concentration-versus-time profile of norelgestromin after patch application on the buttock for three consecutive cycles. Dashed horizontal lines indicate the reference range. C ss steady-state concentrations. Reprinted with permission (13). that clinical efficacy would be maintained even if a scheduled change was missed for as long as two full days. Consecutive Cycles of Use The pharmacokinetics of norelgestromin and EE after application of the contraceptive patch (1 per week) for three cycles (3 weeks/cycle) were determined in an open-label, randomized study (24 participants) (13). Participants wore the patch on the abdomen in one group or the buttock in another group during the sampling periods and at any one of four approved sites (abdomen, buttock, arm, or torso [excluding breasts]) during other time periods for three consecutive cycles. Normal daily activities, such as bathing and exercising, were not restricted during the study. Blood samples were taken before patch application and at various time points during week 1 of cycle 1 and weeks 1 3 of cycle 3. Norelgestromin and EE reached steady-state serum concentrations over three cycles of treatment for the buttock application site, and they remained in their reference ranges over the three cycles of once-weekly wear for three consecutive weeks (Figures 4 and 5) (13). Similar results were achieved at the abdomen application site. Accumulation of norelgestromin and EE was minimal (2% 23% increase in C ss and 17% 36% increase in AUC 0 168h ) beyond week 1 of cycle 1. Thus, the contraceptive patch delivers norelgestromin and EE at steady-state concentrations within their reference ranges throughout three consecutive cycles of treatment, and accumulation is minimal. APPLICATION OF THE CONTRACEPTIVE PATCH AT VARIOUS SITES The pharmacokinetic profile of norelgestromin and EE after application of the contraceptive patch was determined at each of four anatomic sites (abdomen, buttock, upper outer arm, and torso [excluding breasts]) in a four-period, randomized, crossover study (37 participants) (7). The patch was applied to the specified site (one of four) and worn for 7 days, followed by a 1-month washout period, after which another patch was applied to the next site in each participant s randomized treatment (site of application) sequence. Blood samples were drawn immediately before and up to 240 hours after each patch application to determine serum concentrations of norelgestromin and EE. Mean serum concentrations of norelgestromin and EE remained within their reference range during the 7-day wear period, regardless of the site of application (Figures 6 and 7) (7). Absorption of norelgestromin and EE was approximately 20% less and not strictly bioequivalent when the patch was worn on the abdomen compared with the other three sites; however, abdominal patch application was therapeutically equivalent to the other three sites, because mean serum levels remained within the reference ranges. In addition, a previous study demonstrated effective suppression of ovulation by patches worn on the abdomen (14). The investigators concluded that therapeutic levels of norelgestromin and EE result from patch application on the abdomen, buttock, arm, or torso (excluding breasts). FIGURE 5 Mean serum concentration-versus-time profile of ethinyl estradiol (EE) after patch application on the buttock for three consecutive cycles. Dashed horizontal lines indicate the reference range. Reprinted with permission (13). S8 Abrams et al. Contraceptive patch pharmacokinetics Vol. 77, No. 2, Suppl 2, February 2002

7 FIGURE 6 Mean serum concentration-versus-time profile of norelgestromin after successive applications of the contraceptive patch for 7 days at each of four anatomic sites. Dashed horizontal lines indicate the reference range. Reprinted with permission (7). APPLICATION OF THE CONTRACEPTIVE PATCH UNDER CONDITIONS OF HEAT, HUMIDITY, AND EXERCISE The contraceptive patch was evaluated under conditions of heat, humidity, and exercise to determine whether the pharmacokinetics of norelgestromin and EE are significantly affected, possibly leading to a reduction in contraceptive efficacy. The study was a randomized, three-period, sixtreatment, incomplete block design study (15). During each treatment period, participants (n 30) wore the patch on the abdomen for 7 days under one of six conditions (normal activity, sauna, whirlpool, treadmill, cool-water immersion, or a combination of activities), with a 4-week washout phase between each period. Blood samples were collected before and up to 240 hours after each patch application. Mean serum concentrations of norelgestromin and EE FIGURE 7 Mean serum concentration-versus-time profile of ethinyl estradiol (EE) after successive applications of the contraceptive patch for 7 days at each of four anatomic sites. Dashed horizontal lines indicate the reference range. Reprinted with permission (7). FERTILITY & STERILITY S9

8 FIGURE 8 Mean serum concentration-versus-time profile of norelgestromin under conditions of physical exertion and varying temperature and humidity. Dashed horizontal lines indicate the reference range. Reprinted with permission (15). FIGURE 9 Mean serum concentration-versus time profile of ethinyl estradiol (EE) under conditions of physical exertion and varying temperature and humidity. Dashed horizontal lines indicate the reference range. Reprinted with permission (15). S10 Abrams et al. Contraceptive patch pharmacokinetics Vol. 77, No. 2, Suppl 2, February 2002

9 FIGURE 10 Mean serum concentration-versus-time profile of norelgestromin after application of the contraceptive patch, with and without tetracycline administration (data on file, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.). FIGURE 11 Mean serum concentration-versus-time profile of ethinyl estradiol (EE) after application of the contraceptive patch, with and without tetracycline administration (data on file, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.). FERTILITY & STERILITY S11

10 generally remained within the reference ranges during the 7-day wear period for all activities (Figures 8 and 9) (15). No significant treatment effects were observed for norelgestromin, whereas there was a statistically significant treatment effect for EE for AUC 0 240h, but not for C ss. Combination and treadmill activities caused a slight increase in mean AUC 0 240h for EE, but mean C ss for combination and treadmill activities were still within the reference range and did not significantly differ from that seen with normal wear. If the increased levels of EE were due to increased dermal blood flow under conditions of heat, humidity, and exercise, an increase in norelgestromin levels would be expected as well; thus, it is unclear as to what mechanism caused the increases in EE levels. The investigators concluded that mean serum concentrations of norelgestromin were unchanged during all conditions in this trial and that mean serum concentrations of EE did not increase suddenly, did not decrease below the reference range, and generally remained within the reference range. Therefore, the contraceptive patch delivers efficacious concentrations of norelgestromin and EE even under conditions of heat, humidity, exercise, and cool-water immersion. DRUG INTERACTION STUDY WITH THE CONTRACEPTIVE PATCH AND TETRACYCLINE It has been suggested that tetracycline may affect the gastrointestinal absorption of progestins and estrogens when administered orally (16). This raises the question of whether coadministration of the contraceptive patch with tetracycline would affect the pharmacokinetics of norelgestromin or EE. A randomized, open-label, crossover study (24 participants) was performed to test this hypothesis (17). The dosing sequence was 1-week patch alone/1-week patch plus tetracycline HCl (500 mg orally every 6 hours), or 1-week patch plus tetracycline HCl/1-week patch alone, with a 1-month washout period between each treatment. Tetracycline was taken 3 days before patch application and until the patch was removed. Blood samples were collected before and up to 240 hours after patch application. Norelgestromin and EE concentrations did not significantly differ when tetracycline was coadministered with the patch (Figures 10 and 11). Therefore, we conclude that tetracycline will not decrease the efficacy of the contraceptive patch. SUMMARY The 20-cm 2 contraceptive patch systemically delivers mean serum concentrations of 150 g/d of norelgestromin and 20 g/d of EE, achieving concentrations within the established reference range for efficacy ( ng/ml and pg/ml, respectively). Moreover, the contraceptive patch maintains serum concentrations of norelgestromin and EE within these ranges for up to 10 days, suggesting that clinical efficacy is maintained even if a scheduled change is missed for as long as two full days. The patch delivers efficacious serum concentrations of norelgestromin and EE regardless of the location of patch application (abdomen, buttock, arm, or torso [excluding breasts]) and under conditions of heat, humidity, exercise, and cool-water immersion. Coadministration with tetracycline does not affect serum concentrations of norelgestromin or EE. Thus, the contraceptive patch exhibits an excellent pharmacokinetic profile and maintains efficacious serum hormone concentrations under varying conditions. References 1. Corson SL. Efficacy and safety of a monophasic and a triphasic oral contraceptive containing norgestimate. Am J Obstet Gynecol 1994;170: McGuire JL, Phillips A, Hahn DW, Tolman EL, Flor S, Kafrissen ME. Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites. Am J Obstet Gynecol 1990;163: Abrams L, Skee D, Talluri K, Wong F. Bioavailability of 17-deacetylnorgestimate (17D-NGM) and ethinyl estradiol (EE) from a contraceptive patch [abstract no. 961]. FASEB J 2000;14:A Wong FA, Edom RW, Duda M, Tischio JP, Huang M, Juzwin S, et al. Determination of norgestimate and its metabolites in human serum using high-performance liquid chromatography with tandem mass spectrometric detection. J Chromatogr B Biomed Sci Appl 1999;734: PPD Development. Validation report: GC/MS analysis of 17 -ethinyl estradiol and norethindrone in human serum and plasma. Richmond (VA): PPD Pharmaco, Abrams LS, Skee DM, Wong FA, Anderson NJ, Leese PT. Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches. J Clin Pharm. 2001;41: Abrams LS, Skee DM, Natarajan J, Wong, FA, Anderson GD. Pharmacokinetics of a contraceptive patch (EVRA /ORTHO EVRA ) containing norelgestromin and ethinyl estradiol at four application sites. Br J Clin Pharmacol. [In press]. 8. Anderson DC. Sex-hormone-binding globulin. Clin Endocrinol 1974; 3: Briggs MH, Briggs M. Clinical and biochemical investigations of a variable-dose combined type oral contraceptive. Curr Med Res Opin 1977;5: Phillips A, Hahn DW, McGuire JL. Relative binding affinity of norgestimate and other progestins for human sex hormone-binding globulin. Steroids 1990;55: Abrams LS, Skee D, Natarajan J, Lasseter KC, Wong F. Dose proportionality study of a contraceptive patch [abstract no. PI-66]. Clin Pharmacol Ther 2000;67: Abrams LS, Skee D, Bridson WE, Wong F. Pharmacokinetics of a contraceptive patch [abstract no. PI-67]. Clin Pharmacol Ther 2000;67: Abrams LS, Skee DM, Natarajan J, Wong FA, Lasseter KC. Multipledose pharmacokinetics of a contraceptive patch in healthy women participants. Contraception 2001;64: Dittrich R, Parker L, Rosen JB, Shangold G, Creasy GW, Fisher AC, for the ORTHO EVRA /EVRA 001 Study Group. Transdermal contraception: evaluation of three transdermal norelgestromin/ethinyl estradiol doses in a randomized, multicenter, dose-response study. Am J Obstet Gynecol [In press]. 15. Abrams LS, Skee DM, Natarajan J, Wong FA, Leese PT, Creasy GW, et al. Pharmacokinetics of norelgestromin and ethinyl estradiol delivered by a contraceptive patch (Ortho Evra /Evra ) under conditions of heat, humidity, and exercise. J Clin Pharmacol 2001;41: Fazio A. Oral contraceptive drug interactions: important considerations. South Med J 1991;84: Abrams LS, Skee D, Natarajan J, Hutman W, Wong F. Tetracycline HCL does not affect the pharmacokinetics of a contraceptive patch [abstract no. FC ]. Int J Gynecol Obstet 2000;70(Suppl 1):57 8. S12 Abrams et al. Contraceptive patch pharmacokinetics Vol. 77, No. 2, Suppl 2, February 2002